This application is a 371 of PCT/EP 98/07968 filed Dec. 08, 1998.
The present invention relates to the use of carbonic acid for producing a pharmaceutical or cosmetic preparation for topical application for stabilizing or increasing the epidermal ceramide synthesis rate.
The outer boundary layer between a person and his surroundings is formed by the skin. One of the most important tasks of the skin is to form a barrier between external and internal environment. This barrier, which is of crucial importance for maintaining a constant internal environment, is referred to as a permeability barrier.
Numerous skin disorders are associated with a constitutional or acquired disturbance of the epidermal permeability barrier. A stabilization or the physiological building up of the permeability barrier is therefore an important aim of topical treatments and of crucial importance for example for people with a constitutionally sensitive skin (atopic diathesis of the skin), for people with dry skin as well as for preventing occupationally associated skin changes.
Although, in the final analysis, accurate assessment of the importance of all the individual epidermal lipids for maintaining the barrier function is not yet available, numerous investigations exist on the importance of the ceramides, one fraction of the epidermal lipids, for the barrier function. Thus, for example, G. Imokawa et al. (Arch. Dermatol. Res. (1989) 281: 45-51) were able to show that the water-binding function of the horny layer and the water permeability barrier function of the skin are primarily determined by the ceramide lipid fraction.
New findings of lipid research suggest that defects of epidermal lipid metabolism, and in particular a reduction of the amount of ceramides, lead to changes in the cohesion and desquamation of corneocytes. Impairments of the barrier function and conditions with disturbed hornification may be the consequence (O. Braun-Falco, G. Plewig, H. H. Wolff, Dermatologie und Venerologie, 4th edition, 1996, Springer Verlag, Berlin Heidelberg N.Y.).
Disturbances in the lipid pattern in atopic people (with a constitutionally increased skin sensitivity, atopic dermatitis, neurodermatitis, atopic eczema) have been detected in various investigations. Thus, J. Hollmann et al. (H+G (1996) 71: 115-120) were able to detect a reduction in the ceramide content of the horny layer in people with neurodermatitis.
A reduced activity of the enzyme sphingomyelinase was detected in the dry skin of the elderly (T. Yamamura et al., J. Dermatol. Sci. (1990) 1: 79-84). This enzyme is involved in ceramide synthesis, and a reduced activity leads to a deficiency of ceramides.
These investigations indicate that epidermal lipids and, in particular, epidermal ceramides are of central importance in the pathogenesis in particular of skin disorders associated with sebostasis (dry skin) and increased scale formation.
In the pharmaceutical and cosmetic industry various attempts have been made in the past, based on the increasing knowledge about the importance of epidermal ceramides for the barrier function of the skin, to incorporate physiological ceramides in cosmetics and thus introduce them into the skin. The production of such cosmetics is, however, not very profitable because of the technical complexity and the costs of the raw materials (ceramides). In addition, it is still doubtful whether there is in fact any incorporation into the epidermal barrier of ceramides applied topically.
It is known further that irradiation with UV-A and UV-B increases the epidermal ceramide synthesis rate. UV irradiation for skin changes associated with a compromised barrier function shows good therapeutic effects. However, this type of therapy often cannot be employed in the therapy of atopic eczema because a large proportion of atopic people are photosensitive. In addition, in view of the side effects, the risks of UV irradiation must be taken into account in the xe2x80x9ccost-benefitxe2x80x9d assessment of the use of this type of therapy.
A method for the therapeutic treatment of skin by CO2-impregnated water is disclosed in DE 41 24 728. This is intended to treat intractable skin disorders and disturbances of blood flow. No increase in the epidermal ceramide synthesis rate is disclosed.
An increased utilization of oxygen in the skin through topical use of CO2 is also disclosed by D. R. Hartmann et al. in Angiology 48 (4), 1997, pages 337-343.
An improved blood flow through topical use of CO2, and the resulting use for treating skin ulcers and wounds is disclosed by T. Ito et al. in J. Invest. Dermatol. 93 (2), 1989, pages 259-262.
Thus the effect of CO2 on peripheral blood flow disturbances and disorders attributable thereto, such as, for example, chronic ulcers and sores, is known.
Other skin disorders such as atopic dermatitis, and cumulative subtoxic or traumiterative eczemas, are, however, attributable not to blood flow disturbances but, inter alia, to disturbances of lipid synthesis, in particular of ceramide synthesis. There is thus a need for preparations which stabilize or increase epidermal ceramide synthesis.
It is thus an object of the present invention to provide a preparation which stabilizes or increases the epidermal ceramide synthesis rate.
It has now been found according to the invention that the application of carbonic acid or CO2 stabilizes or increases the epidermal ceramide synthesis rate.
The invention thus relates to the use of carbonic acid and/or CO2 for producing a pharmaceutical and/or cosmetic preparation for topical application for stabilizing or increasing the epidermal ceramide synthesis rate.
The stabilizing or increasing of the epidermal ceramide synthesis rate contributes to stabilizing or improving the integrity of the epidermal permeability barrier and thus to reducing the transepidermal water loss and to increasing the relative skin hydration. It is possible in this way, for example, to prevent or treat atopic xeroses, dry skin in the elderly and eczemas due to irritation and contact allergy of the skin.
It is thus possible in general to treat preventively or therapeutically, through a stabilization or increase of the epidermal ceramide synthesis rate, skin disorders due to moisture stress of the skin, such as, for example, a cumulative subtoxic or traumiterative eczema. These include occupational skin disorders, which are predominantly associated with an impaired permeability barrier. In addition, it is possible for a constitutionally increased skin sensitivity (atopic dermatitis, neurodermatitis, atopic eczema) to be treated preventively or therapeutically through a stabilization or increase of the epidermal ceramide synthesis rate.
For the purpose of the present invention, a preparation comprising carbonic acid or CO2 as therapeutic active ingredient means any preparation which directly comprises carbonic acid or CO2 or releases carbonic acid or CO2 on the skin. Possible examples thereof are aqueous compositions which comprise CO2 gas dissolved in-water, such as, in the simplest case, pure carbonated water. The preparation can, for example, also be in the form of a lotion, gel, foam, cream, washing or rinsing composition. Formulas for preparations containing carbonic acid are to be found, for example, in Derwent ref. 84-235086/78.
Likewise suitable are compositions which release carbonic acid only on contact with the skin or shortly before use. These may comprise, for example, compositions which are applied to the moist skin in order to release carbonic acid in a chemical reaction in contact with water. Examples to be mentioned of release of carbonic acid shortly before use are bath additives. These compositions which release carbonic acid only shortly before or on use of the medicament may comprise a carbonate salt (bicarbonate or hydrogen carbonate) such as sodium or potassium carbonate and an organic acid (for example fruit acids such as citric acid or tartaric acid) which release carbonic acid from the carbonate salt in the presence of water. These compositions preferably also comprise a wetting agent so that the reaction to release the carbonic acid starts as quickly as possible when the composition comes into contact with water.
The preparations according to the invention may comprise further conventional, pharmaceutically acceptable additives depending on the form and desired mode of use.
The effective concentration of carbonic acid in the preparation depends on the mode and duration of use and on the disorder to be treated and can easily be determined by the skilled worker.
The content of CO2 gas in carbonated water may range, for example, from 350 mg/l to 1500 mg/l of water. The pH of the preparation achieved by the carbonic acid can be between 5 and 7, preferably at about 5.4.